Influenza is a worldwide public health problem. The present seasonal vaccines are effective in prevention of disease induced by closely matched viruses. However, because of the continuous accumulation of point mutations, genetic reassortment between different subtypes, and non-human influenza virus adaption to humans, mismatch between vaccines and circulating viruses compromises the efficacy of current vaccines and results in increased susceptibility of vaccinated subjects. New vaccine strategies capable to provide enhanced protection by seasonal vaccines against heterologous viruses will have an important impact on public health. We recently reported that microneedle-based skin vaccination with a fusion protein including M2e tandem repeats and the Toll-like receptor (TLR) 5 ligand from bacterial flagellin (4.M2e-tFliC) elicited effective protection against heterosubtypi viruses. We will investigate whether a boost immunization with dissolving polymer microneedles patch delivering redesigned 4.M2e-tFliC to skin after the conventional vaccination, or a microneedle patch co- delivering conventional vaccines and 4.M2e-tFliC, will rapidly broaden the protective efficacy of current seasonal vaccines against an emerging drift variant or even a potential pandemic strain. We will pursue two specific aims: Specific Aim 1. Evaluation of enhanced immune protection against drifted viruses as well as potential pandemic strains in mice. We will test whether a boost immunization with dissolving microneedles delivering 4.M2e-tFliC to skin after conventional immunization, or microneedle co-delivery of split vaccines and 4.M2e-tFliC, will elicit enhanced protection against an emerging drift or potential pandemic variant. Specific Aim 2. Determination of enhanced protection in guinea pigs. As a more relevant animal model to obtain proof-of-concept data for human skin vaccination and prevention of influenza transmission, we will determine: 1) whether a boost immunization with 4.M2e-tFliC-encapsulated dissolving microneedles after conventional vaccination, or microneedles co-delivering split vaccines plus 4.M2e-tFliC to skin, will induce enhanced immune responses conferring protection against heterologous viruses in guinea pigs; and 2) whether the proposed vaccine strategies will prevent contact and aerosol transmission from infected guinea pigs as a donor to mimic natural infection. Overall, our approach is innovative in combining 4.M2e-tFliC encapsulated in dissolving microneedle patches with conventional influenza vaccines, and will provide a promising novel approach to provide additional protection to vaccines when a new drift or pandemic strain is emerging.